NSUN6 inhibitor discovery guided by its mRNA substrate bound crystal structure

IF 4.3 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Structure Pub Date : 2025-01-24 DOI:10.1016/j.str.2024.12.021

Fumei Zhong, Tian Pu, Qian Hu, Mingwei Li, Lei Wang, Suman Wang, Ke Ruan, Yunyu Shi, Beicheng Sun, Yiyang Jiang, Mengqi Lv

引用次数: 0

Abstract

NSUN6 preferentially catalyzes the methylation of cytosine nucleotides in mRNA substrates, which enhances transcription. Dysregulation of NSUN6 catalysis drives the oncogenesis of certain cancers. In this study, we determined the crystal structure of human NSUN6 in complex with its S-adenosyl-L-methionine analog and a bound NECT-2 3′-UTR RNA substrate at 2.9 Å resolution. The complex structure reveals how NSUN6 recognizes the specific CUC[CU]A consensus motif of the substrate and facilitates the methyl transfer from S-adenosyl-L-methionine (SAM) to mRNA. By combining the structural data with nuclear magnetic resonance (NMR)-based fragment screening, a virtual screening, and a further comprehensive biochemical verification, we identified thiamine disulfide as a non-SAM analog lead compound that competes with the CUC[CU]A substrate for binding to NSUN6. Our findings pave the way for the discovery of potent inhibitors for the treatment of NSUN6-driven cancers in the future.

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利用mRNA底物结合晶体结构发现NSUN6抑制剂

NSUN6优先催化mRNA底物中胞嘧啶核苷酸的甲基化，从而促进转录。NSUN6催化的失调驱动某些癌症的肿瘤发生。在这项研究中，我们以2.9 Å的分辨率测定了人类NSUN6及其s -腺苷- l-蛋氨酸类似物和结合的NECT-2 3 ' -UTR RNA底物的晶体结构。复杂的结构揭示了NSUN6如何识别特定的CUC[CU]一个底物的共识基序，并促进从s -腺苷- l-蛋氨酸（SAM）到mRNA的甲基转移。通过将结构数据与基于核磁共振（NMR）的片段筛选、虚拟筛选和进一步全面的生化验证相结合，我们确定硫胺素二硫化物是一种非sam类似先导化合物，可以与CUC[CU] a底物竞争，与NSUN6结合。我们的发现为未来发现治疗nsun6驱动的癌症的有效抑制剂铺平了道路。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Structure 生物-生化与分子生物学

CiteScore

8.90

自引率

1.80%

发文量

155

审稿时长

3-8 weeks

期刊介绍： Structure aims to publish papers of exceptional interest in the field of structural biology. The journal strives to be essential reading for structural biologists, as well as biologists and biochemists that are interested in macromolecular structure and function. Structure strongly encourages the submission of manuscripts that present structural and molecular insights into biological function and mechanism. Other reports that address fundamental questions in structural biology, such as structure-based examinations of protein evolution, folding, and/or design, will also be considered. We will consider the application of any method, experimental or computational, at high or low resolution, to conduct structural investigations, as long as the method is appropriate for the biological, functional, and mechanistic question(s) being addressed. Likewise, reports describing single-molecule analysis of biological mechanisms are welcome. In general, the editors encourage submission of experimental structural studies that are enriched by an analysis of structure-activity relationships and will not consider studies that solely report structural information unless the structure or analysis is of exceptional and broad interest. Studies reporting only homology models, de novo models, or molecular dynamics simulations are also discouraged unless the models are informed by or validated by novel experimental data; rationalization of a large body of existing experimental evidence and making testable predictions based on a model or simulation is often not considered sufficient.